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A 64-year-old man was noted to have icteric sclera but had no abdominal symptoms. CT scans revealed a pancreatic mass with both solid and cystic components. ERCP revealed dilatation of the distal pancreatic ductal system in the head of the pancreas. On gross examination, the main pancreatic duct was dilated, filled with mucin and contained papillary projections. A 2.5 cm tumor mass extended from one aspect of the duct into the pancreatic parenchyma.

Archive Case and Diagnosis:
This case first appeared as Performance Improvement Program in Surgical Pathology (PIP) 2008, and Case 22 is mucinous carcinoma arising in an intraductal papillary mucinous neoplasm.

Criteria for Diagnosis and Comments:
Histologic sections of this pancreatic tumor reveal gross disruption of the pancreatic architecture, with multiple cystically dilated glandular structures in a background of stromal fibrosis. On closer inspection, an intraductal lesion is present which is composed of papillary projections lined by columnar mucinous epithelium. There is moderate architectural disorder within the epithelium, and the cells show mildly enlarged hyperchromatic nuclei, consistent with moderate dysplasia. Associated with this intraductal lesion is a clearly invasive mucinous carcinoma, consisting of ill-defined pools of mucin containing islands of tumor cells which dissect through the surrounding pancreatic tissue. These findings are diagnostic of a mucinous adenocarcinoma arising within an Intraductal Papillary Mucinous Neoplasm (IPMN).

Intraductal papillary mucinous neoplasms of the pancreas were first defined as an entity in the early 1990s. Prior to that time, these lesions were categorized by various names, and may often have been misdiagnosed as other types of mucinous pancreatic lesions. However, since the initial descriptions these lesions have been recognized with increasing frequency. By conservative estimates, IPMNs represent 1-3% of pancreatic exocrine tumors, although more recent literature indicates that they may, in fact, account for up to 7% of all pancreatic neoplasms and roughly 24% of cystic pancreatic tumors. While IPMNs are by definition “intraductal”, an associated invasive carcinoma is present in approximately 30% of patients at the time of diagnosis. The histology of the invasive component can be either usual ductal adenocarcinoma or, more commonly, mucinous adenocarcinoma. The occurrence of an invasive component is believed to be the result of neoplastic progression of the intraductal component along an adenoma-carcinoma sequence.

There is a broad age range for IPMNs, although the majority of cases occur in the 6-7th decade. Interestingly, there is a male predominance, in contrast to mucinous cystic neoplasms of the pancreas, which occur almost exclusively in women. Clinically, patients may present with epigastric pain, pancreatitis, weight loss, or symptoms related to bile duct obstruction. However, they are increasingly detected incidentally at an asymptomatic stage by abdominal imaging for an unrelated indication. Typical CT or MRI findings include mural nodules within a dilated pancreatic duct or an associated cyst. The internal structure of the duct can also be assessed by MRCP or ERCP. A virtually diagnostic finding on endoscopy is extrusion of mucinous material through the ampulla, with a so-called “fish-eye” appearance of the major duodenal papilla.

On gross examination, IPMNs vary significantly in their appearance. Most occur in the pancreatic head and involve the main pancreatic duct and its immediate branches. Usually, dilation of the proximal ductal system is present with abundant intraluminal mucin. The tumor often appears cystic and multiloculated. Typically, involvement of the duct system is localized, although some instances of diffuse involvement have been reported. The latter observation has been invoked to explain recurrence after seemingly complete resection in some patients. Occasionally, IPMNs involve smaller peripheral ducts, often in the uncinate process, and are known as “branch-duct”-type IPMNs. These variants may be biologically distinct from their main duct counterparts, although more investigation is needed in order to better define the differences. If an invasive carcinoma is present, there may be gross evidence of desmoplasia or mucin dissection into surrounding pancreatic parenchyma. However, foci of ruptured mucin near involved ducts without accompanying tumor cells does not warrant a diagnosis of invasive carcinoma. The presence of foci of abnormal mucin-producing tissue distant from the involved duct or outside of the pancreatic parenchyma is particularly concerning for invasion.

Histologically, IPMNs are distinctive lesions composed of complex papillary epithelial structures within dilated ducts. The lining epithelium is mucinous, and can be subdivided into four histologic subtypes: intestinal (the most common), pancreatobiliary, oncocytic, and gastric. At present, ongoing research is defining biologic and prognostic differences between these groups. Once a diagnosis of IPMN is made, the lesion must be graded based on the degree of dysplasia of the lining epithelium. Those with minimal or no dysplasia and orderly tall columnar mucin-secreting cells are classified as “intraductal papillary mucinous adenoma”. Those with moderate dysplasia are classified as “borderline intraductal papillary-mucinous neoplasm”. Moderate dysplasia is defined architecturally by epithelial pseudostratification and formation of pseudopapillary structures, and at a cellular level by loss of epithelial polarity, nuclear crowding, enlargement, and hyperchromasia. IPMNs with severe dysplasia (carcinoma in-situ) are termed “intraductal papillary-mucinous carcinoma, non -invasive”. Architecturally, severe dysplasia is represented by cribriform growth, intraluminal epithelial budding, and loss of epithelial polarity. At the cytologic level, significant nuclear enlargement, hyperchromasia, and pleomorphism are typically present. Mitoses may be seen in the more superficial levels of the epithelium. Importantly, mucin may be depleted or even absent from lining epithelial cells in the setting of severe dysplasia.

Although grading the intraductal component is important, the most crucial prognostic feature is the presence or absence of an associated invasive carcinoma. Therefore, IPMNs must be extensively examined in order to exclude an invasive component. In some cases, the entire lesion must be submitted for histology. If invasive carcinoma is the dominant finding, then the diagnosis should be one of invasive carcinoma, with mention of an associated IPMN. As mentioned earlier, the invasive component is most often a mucinous carcinoma, which typically arises from the intestinal-type of IPMN. However, ordinary ductal carcinomas are also seen. The distinction between these two types of invasive carcinoma is important in predicting long-term survival (see below).

Immunohistochemical staining varies by epithelial subtype. In the intestinal-type lesions, the epithelium expresses MUC2 and CDX2, but is negative for MUC1. The pancreatobiliary type expresses only MUC1. Oncocytic lesions express MUC1 and MUC2 variably, although there are relatively few cases available for comparison. Finally, gastric-type lesions express MUC5, while MUC1, MUC2, and CDX2 positivity are rare. At the molecular level, IPMNs frequently lack the mutations that characterize most pancreatic tumors of ductal origin, such as KRAS, p16, TP53 and the loss of DPC4.

The differential diagnosis of IPMN includes other cystic lesions of the pancreas, such as pancreatic mucinous cystadenoma, mucinous cystadenocarcinoma and serous microcystic adenoma. The principle distinction is based on the presence or absence of communication of the tumor with the ductal system. Other features supportive of mucinous cystadenoma include female gender, location in the body or tail of the pancreas, and the presence of ovarian-type stroma. Mucinous cystadenocarcinoma is defined by invasion and the aforementioned lack communication with the ductal system. Serous microcystic adenoma is easily distinguished on microscopy by the honeycomb architecture and lack of mucin in lining cells. In invasive IPMN, the invasive component can overgrow the intraductal elements such that origin in an IPMN is difficult to recognize. Another entity which can cause confusion is a mucin-producing duodenal ampullary adenoma with intraluminal extension into the pancreatic duct. Gross localization of the main tumor mass to the ampulla and the presence of surrounding ampullary epithelial dysplasia are helpful in this setting.

Overall survival for patients with IPMN is approximately 83% at 5 years. This number is near 100% for IPMNs of the adenoma and borderline type, with a slightly worse prognosis for IPM carcinoma, non-invasive in some series. For those patients with an invasive component, the overall 5-year survival rate drops significantly to between 36-46%. Among this group, mucinous (colloid) carcinomas fare better with a nearly 57% survival rate.

Treatment consists of surgical resection, typically pancreaticoduodenectomy as these lesions usually arise in the head of the pancreas. As the tumor can spread along the ductal system, assessment of surgical margins is important. Most cases of recurrence are attributed to tumoral extension to the margin of excision. However, some authors believe that the stimulus for IPMN formation affects the entire duct system, putting any remaining ductal epithelium at risk of neoplastic transformation and thus tumor “recurrence.”